Perillyl alcohol, a terpene, occurs naturally and has antimicrobial and anticancer properties. Hydrogenation of perillyl alcohol provides 4-isopropyl cyclohexanemethanol, which is a valuable fragrance ingredient having a fresh, clean odor reminiscent of white petals and flower blossoms.
Synthetic approaches to perillyl alcohol have been reviewed (see U.S. Pat. Nos. 3,993,604 and 5,994,598) and fall into three groups. In a first approach, a terpene hydrocarbon (α-pinene, β-pinene, or limonene) is oxidized using an equimolar amount of a toxic or explosive reagent (benzoyl peroxide, lead tetraacetate, or selenium dioxide). U.S. Pat. No. 3,956,404, which uses benzoyl peroxide, is illustrative.
A second approach prepares perillyl alcohol by isomerizing β-pinene oxide (see, e.g., U.S. Pat. Nos. 3,993,604; 4,306,099; and 5,994,598). These methods use an acidic catalyst, give low yields of the desired alcohol, and generate a large amount of wastewater. They often produce mixtures of isomers resulting from double bond migrations, and the by-products are difficult to remove. Some of the methods produce disubstituted derivatives that require an additional step to convert them to perillyl alcohol.
In yet another approach, 1,2-limonene monoxide (hereinafter “LMO” or “limonene oxide”) is used as the starting material. A mixture of cis- and trans-LMO is isomerized to produce, respectively, trans-isocarveol and cis-isocarveol:

The isocarveols are converted into ester or other derivatives that are in turn isomerized to perillyl alcohol derivatives. Finally, the perillyl alcohol derivatives are hydrolyzed to produce perillyl alcohol. For examples of this approach, see U.S. Pat. Nos. 3,993,604 and 3,957,856; Synth. Commun. 18 (1988) 1905, and J. Chem. Research (S) (1977) 304. Interestingly, the latter reference indicates that the isocarveols cannot be isomerized directly to perillyl alcohol, which is consistent with our failure to find any reference teaching such a direct isomerization.
Although a mixture of cis- and trans-limonene oxide is readily available as a starting material, the need to derivatize isocarveols and subsequently remove the ester or other protecting group undermines the value of the third approach. Ideally, perillyl alcohol could be produced directly from the isocarveols in a commercially viable process.
Assuming that such a direct isomerization is even possible, which isocarveol isomer, cis- or trans-, is the better starting material? Distillation is impractical for separating cis- and trans-LMO, and commercially available limonene oxide contains 50-65% of cis-LMO and 35-50% of trans-LMO. If one isocarveol isomer is, in fact, better than the other for making perillyl alcohol, how can the preferred isomer be made selectively from a mixture of cis- and trans-LMO?
In U.S. Pat. No. 6,835,686, we described a method for isomerizing a mixture of cis- and trans-LMO to give isocarveols (compound 3). See, in particular, Example 45, which utilizes 1.7 wt. % of chromium octoate catalyst, 0.5 wt. % of a phenolic activator, and reflux at greater than 220° C. for 2.5 hours such that conversion of the combined mixture of LMO isomers exceeds 99.5% (see Table 2 of the '686 patent). No information is provided about the relative amounts of trans- and cis-isocarveols obtained; however, a high conversion of both cis- and trans-LMO to the isocarveols is evident from the overall quantitative conversion.
Numerous processes are known for isomerizing allylic alcohols. One such process uses a Group 5 metal catalyst such as ammonium metavanadate to (NH4VO3) or the like to effect the transformation (see, e.g., U.S. Pat. Nos. 3,925,485 and 4,254,291). Known processes of this type, however, typically involve isomerization of open-chain tertiary allylic alcohols to secondary and primary alcohols. The reaction has not been applied to cyclic, secondary alcohols such as cis- and trans-isocarveol.